Section 1 Normal Sleep and Its Variants
1.1 Sleep–Wake Mechanisms and Neurophysiology
Ventrolateral preoptic nucleus (VLPO) contains cells that contain the inhibitory neurotransmitters GABA and galanin (GAL). (Atlas, p 21)
REM-off neurons (in the ventrolateral periaqueductal gray (vlPAG) and lateral pontine tegmentum (LPT) receive inputs from the VLPO and orexin neurons. (Atlas, p 23)
Cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei (PPT-LDT) are REM-on by inhibiting the LPT. Because these neurons are not in turn directly inhibited by the LPT they are external to the switch. (Atlas, p 23)
REM atonia is produced by SLD neurons via glutamatergic spinal projections to interneurons that inhibit motor neurons in the spine by both glycinergic and GABAergic mechanisms. (Atlas, p 23)
A 20-Year-Old Student Pulling an All-Nighter
3 Which neurotransmitters are not actively involved in keeping his brain aroused?
B Acetylcholine from cholinergic neurons in pedunculopontine tegmental and laterodorsal tegmental nuclei
4 The arousal system causes arousal of the student’s cerebral cortex by pathways directly connected through which structures?
6 Which chemical is accumulating in his central nervous system and causing the sleepiness before he drinks coffee?
9 Her pediatrician believes that she is exhibiting symptoms of a neurologic disease, perhaps multiple sclerosis, and would like to have a spinal tap done. If a spinal tap were performed, what cerebrospinal fluid abnormality would likely be present?
11 The patient’s awakening during the night, feeling unable to move, and sensing that someone is in the room are characteristic of:
1 A. Exams (self-assessment or board) often begin with an icebreaker, a question everybody should know the answer to. It is important to know the big picture about the mechanisms playing a role in arousal and initiation of sleep. In 1935, Fredric Bremer, a pioneer in sleep research, showed that if a transection is made between the pons and midbrain (the preparation is called cerveau isolé, literally “isolated brain” in French) there is no arousal and the animal is comatose. If a transection is made between the lower medulla and the spine, the animal is able to demonstrate wakefulness and sleep. This preparation is known as l’encéphale isolé. L’encéphale refers to all the nervous system structures in the cranial vault or skull. In 1949, Moruzzi and Magoun showed that stimulating the structures of the rostral pontine reticular formation (basically in the area between Bremer’s two transections) produced a desynchronized (or awake) EEG. This area of the brainstem became known as the ascending reticular activating system. Atlas, p 21
2 D. This question is a follow-up to the question dealing with the ascending reticular activating system (ARAS). The ARAS begins in the medulla and ascends into the pons and midbrain. This is a type of question where “all of the above” is often correct. Atlas, p 21
3 C. There are many chemicals and parts of the brain mentioned that might make your eyes glaze over. It is desirable to know the sleep-promoting systems and the wake-promoting systems (they are reviewed in the Summary that follows). This type of question is in fact easy because you can often get the right answer by process of elimination. When confronted with such a question, don’t panic; look for terms you know and start from there. In this example you need to know any component of the sleep switch (this includes the ventrolateral preoptic nucleus [VLPO], whose cells contain the inhibitory neurotransmitters GABA and galanin [GAL]), or you might have to generalize from information you learned from an entirely different topic. For example, you might have remembered that GABA has something to do with sleep from understanding hypnotics. You always know more than you think. Atlas, p 21
4 D. Again, analyze the question and you will realize that only one of the answers has anything to do with pathways going into the cerebral cortex. There are two pathways of arousal into the cortex from the ARAS: a dorsal route via the thalamus (associated fact: site of spindle formation) and a ventral route via the basal forebrain and the hypothalamus. The basal forebrain is a ventral structure, and the hypothalamus is ventral and below the thalamus. The hypothalamus is right behind the optic chiasm (associated fact: the suprachiasmatic nucleus, the “conductor” of the circadian system “orchestra,” is here) and is above the pituitary gland. The hypothalamus secretes many endocrine-releasing factors and, because of its location and function, it links the endocrine and circadian systems. Atlas, p 21
5 A. All these chemical entities are involved in regulation of hunger and/or energy. Leptin, secreted by fat cells, inhibits hunger. Ghrelin, produced by cells in the stomach, increases hunger. Insulin is produced in response to high glucose levels. Orexin (also called hypocretin) is produced by cells in the lateral and posterior hypothalamus and stimulates hunger and wakefulness. Narcolepsy patients have reduced orexin-producing cells and are sleepy as a result.
6 C. It is believed that adenosine, an inhibitory neurotransmitter, increases in the nervous system with prolonged wakefulness.
7 C. Caffeine, a xanthine, is a competitive inhibitor of adenosine because it is an antagonist of adenosine receptors in the nervous system. It has structural similarities to adenosine. The net result of blocking the effect of a compound that inhibits CNS function is to stimulate the CNS and promote wakefulness.
8 D. Theophylline is a xanthine that is sometimes used to treat asthma. It is also in the xanthine family of compounds as is caffeine (actually it is one of the metabolites of caffeine) that also relax bronchial smooth muscle, increase contractility of the heart, and can increase heart rate and blood pressure. Theophylline affects the nervous system through its action as an adenosine receptor antagonist.
9 A. From the symptoms mentioned, this is most likely a case of narcolepsy. Each of the factors mentioned can promote sleepiness or sleep. Although rarely tested for clinical purposes, analysis of cerebrospinal fluid in narcoleptics has shown a striking reduction of hypocretin compared to controls.
10 B. The unintended transition from wake to sleep is related to the fact that hypocretin neurons project widely in the cerebral cortex and stabilize wakefulness. The lack of these neurons results in wake and sleep instability. Atlas, p 22
11 C. This is a classic description of sleep paralysis. Patients awaken, usually from a dream, often with the perception that there is someone else in the room, sometimes a frightening devil-like creature. These events are likely the persistence of REM phenomena (dreaming and motor inhibition) persisting into wakefulness. Atlas, p 108
12 C. The motor weakness is related to the neurons of the sublaterodorsal (SLD) nucleus inhibiting motor spinal neurons by glycinergic and GABAergic mechanisms. Atlas, p 23 Interestingly the motor neurons projecting to the diaphragm are spared, and thus the motor atonia does not affect breathing.
13 A. The sleepiness seen with influenza is seldom caused by infection of cells in the nervous system but by the effect of cytokines that are a response to the infection. Cytokines are proteins and glycoproteins that behave like neurotransmitters and are commonly expressed during infections. The remaining three answers (B, C, D) are mechanisms that likely do play a role in the sleepiness. Atlas, p 34
14 D. Infections typically increase NREM sleep (and can increase slow-wave sleep) and reduce REM sleep. Atlas, page 34
15 A. This is the type of question where you might not know much about the topic but can get the right answer from associated bits of knowledge. Orexin is not a cytokine, and leptin, which might be considered a cytokine, is produced by fat cells, and fat cells have nothing to do with infections. Thus, knowing either of these facts could help point to the correct answer. The other answers (B, C, D) are cytokines that can be increased in infections. Atlas, p 34
16 A. The sleepiness can start abruptly with infections, sometimes within hours. It is related to cytokine production and will last days to a few weeks as the infection resolves. However, the reader might have read something about encephalitis lethargica in the distant past and wonder whether that might be a correct answer. It is not. Encephalitis lethargica is an encephalitis that affects the junction of the posterior hypothalamus and the midbrain, producing severe hypersomnolence (hence the name von Economo’s sleeping sickness, for the neurologist who described this finding). Encephalitis lethargica can also cause symptoms such as an inability to move or speak. The cause of the illness that was seen in epidemic form (and was last seen as an epidemic in the 1920s) is unknown. Autoimmune and infectious causes have been suggested but never proved. Most victims of encephalitis lethargica died in a coma. Some of the survivors entered into a rigid, Parkinson-like state. This clinical picture was eloquently described by the neurologist Oliver Sacks, in his 1973 book Awakenings, and also portrayed in the 1990 movie of the same name starring Robin Williams.
Summary
Sleep Switch
Ventrolateral preoptic nucleus (VLPO) contains cells that contain the inhibitory neurotransmitters GABA and galanin (GAL). (Atlas, p 21)
REM Switch
REM-off neurons (in the ventrolateral periaqueductal gray (vlPAG) and lateral pontine tegmentum (LPT) receive inputs from the VLPO and orexin neurons. (Atlas, p 23)
Structures and Neurotransmitters That Affect REM
Cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei (PPT-LDT) are REM-on by inhibiting the LPT. Because these neurons are not in turn directly inhibited by the LPT they are external to the switch. (Atlas, p 23)
Clinical Correlations
REM atonia is produced by SLD neurons via glutamatergic spinal projections to interneurons that inhibit motor neurons in the spine by both glycinergic and GABAergic mechanisms. (Atlas, p 23)
1.2 Circadian Mechanisms and Neurophysiology
2 Where are the cells located that play the main role in synchronizing the circadian timing of this patient’s sleep–wake pattern?
3 Which of the following is involved in synchronizing the student’s circadian system? Pick the best answer.
7 This patient was studied for several nights in a circadian rhythm laboratory under continuous dim light conditions. It was found that his core body temperature nadir occurred regularly every 20.2 hours. This finding is evidence for which of the following?
